Abstract 3413: A pan-cancer atlas of genomic, epigenomic and transcriptomic alterations in the TGF-β pathway

The TGF-β pathway is a multifunctional signaling cascade with context-dependent roles in diverse biologic processes, including tumor promotion or suppression, metastasis, stem cell homeostasis, and immune suppression. Due to its highly context-dependent nature, decoding functional outcomes of the TGF-β pathway in specific tissues is highly challenging. Here, we present comprehensive genomic, transcriptomic and epigenomic analyses of the TGF-β pathway identified by 44 core pathway genes across 33 TCGA tumor types and 9125 samples. The core pathway genes involve TGF-β like ligands, receptors, intracellular SMAD molecules and adaptors. Although individual core pathway genes were rarely mutated or copy number altered in different cancer types, 41% of all samples have at least one genomic alteration in the TGF-β pathway, predominantly in the form of mutations. We identified a highly conserved TGF-β downstream gene expression signature associated with alterations in core pathway genes, suggesting that the alterations in the pathway have shared functional consequences. We observed a significant enrichment of the genomic alterations in gastrointestinal cancers (GI) with a distinct gene expression signature. The newly identified gene expression signature (over- or downregulation of key TGF-β downstream genes) in pan-cancer cohort was associated with significantly poor prognosis, particularly when it co-occurred with genomic alterations in the core pathway. Analysis of mutational hotspot sites revealed 6 genes with hotspots recurring in at least 9 (up to 78) mutational incidences. The hotspot mutations were also highly enriched in GI cancers. We identified previously characterized cancer mutation sites on SMAD4 and SMAD2 as hotspots mainly in GI cancers. We hypothesized novel functions to two of the newly identified hotpot sites through structural and trancriptomic analyses, and two other novel hotspot sites in the pathway await functional characterization. miRNA and epigenomic analyses revealed that TGF-β pathway activity is limited by epigenetic silencing or miRNA expression, especially in cancers with very low pathway gene expression levels. This multidimensional study provides the multifacefed landscape of TGF-β signaling in both individual disease and pan-cancer settings to guide future functional and therapeutic studies of this key cancer pathway. Citation Format: Anil Korkut, Sobia Zaidi, Rupa Kanchi, Ashton C. Berger, Gordon Robertson, Lawrence N. Kwong, Mik